JPS6039271B2 - α-(p-isobutylphenyl)-α-alkylthioacetic acid and its ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (where RI is a lower alkyl group and R2 is hydrogen or a lower alkyl group).

) Q-(p-isobutylphenyl)-1Q-alkylthioacetic acid and its ester. The compound of the present invention represented by the general formula (1) can be easily converted into Q-(p-isobutylphenyl)propionic acid and its ester by methylating its Q position, hydrolyzing it if desired, and then reductively desulfurizing it. can lead to (
(See reference example below). This compound is called ibuprofen and is known to have anti-inflammatory, analgesic, and antipyretic effects. Conventionally, many methods have been proposed for producing ibuprofen, and typical examples thereof are as follows. 1) The corresponding malonate ester was prepared by reacting p-isoptylphenylacetate with an alkyl carbonate in the presence of a base, and then the malonate ester was methylated with methyl iodide and hydrolyzed. A method for obtaining the desired propionic acid by subsequent thermal decomposition (Japanese Patent Publication No. 1973-
7491), 2) By the action of potassium cyanide and ammonium carbonate, p-isobutylacetophenone is first converted into the corresponding hydanthin, which is hydrolyzed to form a Q-amino acid, further alkylated to form a dialkylamino compound, and then reduced to form Q. -(p-isobutylphenyl)
Method for synthesizing propionic acid (Japanese Patent Publication No. 47-18105
3) The Darzen reaction of p-isobutylacetophenone and monochloroacetate yields the corresponding epoxycarboxylic acid ester, which is hydrolyzed and then decarboxylated to produce Q-(p-isobutylphenyl)propion. Examples include a method of forming an aldihyde and then oxidizing it to obtain the desired propionic acid (Japanese Patent Publication No. 47-12455).

However, all of these conventional methods use p-isobutylacetophenone as a starting material. p-Isoptylacetophenone is a Fried mixture of isobutylbenzene and acetyl chloride.
It can be produced by the el-Crafts reaction, but at this time, aluminum chloride is used in an amount equal to or more than the same mole as the raw material compound, so in the case of mass production, isolation of the product is a waste because of the large amount of aluminum hydroxide generated in post-processing. Processing becomes a huge problem. As a result of intensive studies to overcome this point of view, the present inventors have discovered the compound of the present invention, which can be easily produced using p-isobutylbenzaldehyde as a starting material and is extremely useful as a precursor of ibuprofen. This is what I found. That is, the compound of the present invention can be produced according to the following formula.

First step (0→m) In this step, p-isobutylbenzaldehyde (b) and formaldehyde mercaptal S-oxide are reacted in the presence of a base.

If desired, common organic solvents such as dimethylformamide, tetrahydrofuran, dioxane, methanol, ethanol, benzene, etc. can be used as reaction solvents. In addition, as the base, relatively strong bases such as sodium hydride, potassium, t-butoxide, Triton B, sodium hydroxide, potassium hydroxide, etc. are preferable;
At 0oo, the reaction proceeds smoothly. Second step (m→N) In this step, the ketene mercaptal S-oxide (m) obtained above is reacted with thionyl chloride.

In carrying out this step, the raw materials are used in approximately equimolar amounts, and preferably methylene chloride, chloroform,
The reaction is carried out in an aprotic solvent such as tetrahydrofuran, ether, or benzene. The reaction is -1000
The temperature is preferably -30 oo to room temperature, from the viewpoint of ease of operation. Further, it is preferable that a base be present in order to scavenge by-produced hydrogen chloride. As the base, organic bases such as pyridine and triethylamine can be suitably used. Third step (W→1) This step combines Q-chloroketene mercaptal (N) formed in the previous step with the general formula R20 (wherein R2 is hydrogen or a lower alkyl group).

) is required to react with water or alcohol represented by () in the presence of an acid. As the acid, inorganic acids such as sulfuric acid, perchloric acid, hydrogen chloride, and hydrogen bromide, and organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, and trichloroacetic acid can be suitably used. The amount of acid used is sufficient to be the so-called contact amount. In carrying out the third step, there is no problem in using a solvent that does not participate in the reaction, but an excess amount of water or alcohol used as a reaction reagent can be used as a solvent. Although the reaction proceeds smoothly at a temperature of room temperature to 150 pm, it is preferable to carry out the reaction at the reflux temperature of the reaction system from the viewpoint of ease of operation. Furthermore, the ester compound formed when alcohol is used as a reaction reagent can be hydrolyzed by a conventional method to lead to the corresponding carboxylic acid. The present invention will be explained in more detail below using Examples and Reference Examples. Example 1 p-isobutylbenzaldehyde 486-9 and formaldehyde dimethyl mercaf.

450 parts of tar S-oxide was dissolved in 1 part of t-butanol, 2.0 parts of a solution of potassium t-butoxide in t-butanol (0.608N solution) was added thereto, and the mixture was stirred at room temperature for 12 hours. After 0.5 ml of water was added to the reaction mixture, 50 ml of methylene chloride was added and dried over trinitrogen. After removing the desiccant, the solution was concentrated under reduced pressure and the oily residue was purified by column chromatography (silica gel, methylene chloride) to obtain 1-methylsulfinyl-1-methylthio-2-(p-
9 of 701 was obtained (isobutylphenyl)ethylene. Yield 87%. The sample for analysis was prepared by simple distillation (oil temperature 16
0-17000/0.02 mm day g). IR(
neat): 1610, 1510, 1470, 1420
, 1065,950,800C 11. NMR (CDC
L): 60.91 (d, bait, J: 6HZ), 1.5-2
．． 2 (m, IH), 2.33 (s, pan), 2.71 (d
, 2 days, J = 7 days 2), 2.76 (s, thin), 7, 18
17.81 (A2B2q, 4H), 7.59 (s, IH
). C. 4 days 2.

Calculated value as OS2: C62.64, day 7.51, S2
3.89%. Measured value: C62.32, Sun 7.48, S2
4.07%. Example 21-Methylsulfinyl-1-Methylthio-2-(p-isobutylphenyl) 701 parts of ethylene Dissolved in 2 parts of chloroform, added 0.50 parts of triethylamine, and added 380 parts of thionyl chloride while cooling on ice. A chloroform solution (5 volumes) was added over 1 minute.

After cooling on ice for another 30 minutes, chloroform was added to bring the total volume to 30, and the mixture was washed with water (twice at 10°C). After drying, the residue was concentrated under reduced pressure and purified using column chromatography (Florisil, benzene) to obtain 1,1-pis(methylthio)-12-chloro-2-(p-isobutylphenyl)ethylene 628. was obtained as a colorless oil. Yield 84%. Samples for elemental analysis are prepared by simple distillation [115
~125qo (bath temperature)/0.02hmHg].

IR (neat): 1505, 1470, 860, 85
0,820,795 760,745 佽-1, NMR(
CDC13): 60.89 (d, thin, J=9HZ), 1
-6~2-〇<m, IH), 2-12 (S, thin), 2.
41 (s, milk H), 2.44 (d, 2 days, J=7HZ)
, 7.07-7.26 (A2B2q, 4H). Mass spectrometry (m/e): 288 (M112), 286 (reference peak, M+), 245, 243, 57. C, 4th, 9CIS
Calculated value as 2: C58.61, day 6.68, CI12
．． 36%. Measured value: C58.69, day 664, CI12
．． 34%. Example 31,1-bis(methylthio)-2
-Chloro-2-(p-isobutylphenyl)ethylene 5
Part 9 of 92 was dissolved in 6 parts of anhydrous methanol, 0.1 parts of a saturated methanol solution of hydrogen chloride was added thereto, and the mixture was heated under reflux for 5 hours.

After concentration under reduced pressure, column chromatography (silica gel,
Benzene) to give methyl Q-methylthio(p-isobutylphenyl)acetate 471-9 as a colorless oil. Yield 90%. A sample for elemental analysis was obtained by simple distillation [15-125 pm C/0.1 mmHg]. IR (neat): 1745, 1150, 10
10 skin-1, NMR (CDC13): 60.89 (d,
Navy blue, J: 6HZ), 1.5-2.1 (m, IH), 2.
06 (s, general), 2.43 (d, but J=7HZ), 3
．． 73 (s, SH), 4.47 (s, IH), 7.0~
7.5 (nB2q, 4H). Mass spectrometry (m/e): 25
2 (M10), 205, 193 (reference peak). Calculated value as C, 4th 2002G: C66.63, day 7.99, SI2.71%.
Measured values: C66.56, day 7.88, SI2.47%.
Example 4Q-methylthio (p-isobutylphenyl)
Dissolve 280 parts of methyl acetate in 4 parts of 1,2-dimethoxychetane, add 2 parts of water and 305 parts of sodium hydroxide, and add 9 parts of sodium hydroxide.
was added and incubated at room temperature for 19 hours.

30% of water was added, acidified with egg sulfuric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then separated by column chromatography (silica gel, methylene chloride) to obtain Q-methylthio(p-isobutylphenyl)acetic acid 238-9 as a colorless oil. Yield 90%. This stuff eventually crystallized. Melting point: 58-59oo (from n-hexane). IR(KB
r): 3300-2400, 1710 (sh), 170
0 (Sh), 1692 skin-1, NMR (CDC13):
60. machine (d, thin, J=6HZ), 1.5-2.1 (m
, IH), 2.08 (s, 3H), 2.41 (d, 2 days, J = 7HZ), 4.4 $ (IH), 6.9-7.5 (
A2B, 4H), 10.19 (broad, IH).
Mass spectrometry: m/e238 (M10), 193 (basep
eak), 191, 149. Reference Example 1 Methyl Q-methylthio(p-isobutylphenyl)acetate 471 was dissolved in anhydrous dimethylformamide and 75% sodium hydride (containing 65%) was added while cooling on ice.

Hydrogen generation was immediately observed. After about 1 female was fed, 0.25 methyl chloride was added, and the eggs were kept on ice for 30 minutes and then at room temperature for 40 minutes.

Aqueous ammonium chloride solution (0.5/30) was added and extracted with ether (3 times over 20). The organic layer was washed with water (10 times twice), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane-benzene) to obtain methyl Q-methylthio-Q-(p-isobutylphenyl)propionate as a colorless oil. Yield 85
%. Boiling point 118-12000/0.1mmHg. IR(
neat): 1735, 1245, . 105C 11.
NMR (CDC13): 80.88 (d, pan, J=6H
Z), 1.78 (s, 9H), 1.97 (s, general), 1
．． 5-2.0 (m, IH), 2.45 (d, group, J=7
HZ), 3.76 (s, wide), 7.0-7.5 (A2B
2q, 4H). Mass spectrometry: 266 (M+), 251-
219 (reference peak), 207, 191, 159. C,
Calculated value as 2202S on 5th: C97.62, 8.33 on day, SI2.04%.
Measured value C67.54, day 8.22, SI2.67%. Reference Example To 420 parts of methyl 2Q-methylthio-Q-(p-isobutylphenyl)propionate, 2 parts of water and 4 parts of methanol were added.

Add 280 grams of potassium hydroxide to this and hold at 60°C for 2 and a half hours.
I worshiped the lights. Add 30 parts of water to this and add 10 parts of methylene chloride.
Extracted with '. The aqueous layer was adjusted to approximately pH by adding concentrated hydrochloric acid, extracted with ether (3 times at 20° C.), and dried with anhydrous sodium sulfate. Ether was removed by concentration under reduced pressure to obtain crude product 394 of Q-methylthioQ-(p-isobutylphenyl)propionic acid as an oil. Yield 9
9%. This product eventually crystallized. This was recrystallized from water-methanol to obtain colorless crystals with a melting point of 89-9. IR (KBr): 3000-2500, 1695,
11 of 1295, 1275, 940C. NMR (CDC
13): 60-90 (d, Mother's Day, J = 9HZ), 1.
5-2.0 (m, IH), 1.80 (s, thin), 2.0
2 (s, spots), 2.46 (d, 2 days, J = 7 days 2), 7
．． 0 to 7.5 (A2B2q, 4H), 13.9 (S, I
H). C, 4 days 2.

Calculated value as 02S: C66.63, day 7.99, SI2.71%.
Measured values: C66.85, day 7.76, SI2.97%.
Reference Example 387 pieces of Q-methylthio-Q-(p-isobutylphenyl)propionic acid were dissolved in 3 parts of acetic acid, 200 m9 of zinc powder was added, and the mixture was heated under reflux for 2 hours.

Further, 200 parts of zinc powder was added and the mixture was heated under reflux for 1 hour.
After removing the zinc powder from agglomerating, it was heated under reflux again for 2 hours. After adding 30 parts of water and 20 parts of ether to separate out insoluble materials, concentrated hydrochloric acid was added to bring the pH to about 100 ml, followed by extraction with ether (20 parts x 4 times), washing with water (10 parts on the table), and drying with ramie. Concentrate under reduced pressure to remove ether and acetic acid to give Q-(p
-isobutylphenyl)propionic acid 319-9 was obtained as a clear oil. NMR of the crude product and GLC after methylesterification with diazomethane (SE301
0%, lm, 180 ko○), it was found that it was almost a pure product. Crude yield: 100%. When a small amount of authentic crystals were added to this crude product, it crystallized. Recrystallization from n-hexane gave colorless crystals with a melting point of 74-76 oo. Incidentally, the IR and NMR spectra of this product matched those of the product.

Claims (1)

[Claims] 1 α-(p-isobutylphenyl)-α-alkylthioacetic acid and its ester represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a lower alkyl group] and R^2 is hydrogen or a lower alkyl group. ]. 2. The compound according to claim 1, wherein R^1 is a methyl group.